Hyperlipidemia
Frederick F. Samaha
Daniel J. Rader
Large epidemiologic studies such as the Framingham Heart Study (1) and the Multiple Risk Factor Intervention Trial (MRFIT) (2) suggest a relationship between serum cholesterol and coronary heart disease (CHD). Subsequently, multiple prospective, randomized, controlled clinical trials have demonstrated the clinical benefit of cholesterol reduction, in both the secondary prevention and primary prevention of cardiovascular events (see later discussion). These trials have played an important role in the evolution of our treatment of hyperlipidemia.
The clinical management of patients with hyperlipidemia requires a general working knowledge of normal lipoprotein metabolism (3). Lipoproteins transport cholesterol and triglycerides within the blood. They contain a neutral lipid core consisting of triglycerides and cholesteryl esters surrounded by phospholipids and specialized proteins known as apolipoproteins. The five major families of lipoproteins are chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Chylomicrons are the largest and most lipid-rich lipoproteins, whereas HDL are the smallest lipoproteins and contain the least amount of lipid. Disorders of lipoprotein metabolism involve perturbations, which cause elevation or reduction of one or more lipoprotein classes. Many of these disorders increase risk of premature atherosclerotic cardiovascular disease. The remainder of this chapter will focus on the identification, diagnosis, and clinical management of patients with lipid disorders, especially regarding the prevention of atherosclerosis and its associated clinical events.
Apolipoproteins are required for the structural integrity of lipoproteins and direct their metabolic interactions with enzymes, lipid transport proteins, and cell surface receptors. Apolipoprotein B (apoB) is the major apolipoprotein in chylomicrons, VLDL, IDL, and LDL. Apolipoprotein A-I (apoA-I) is the major apolipoprotein in HDL. Lipoprotein receptors bind these apolipoproteins on the lipoprotein particles. The best understood lipoprotein receptor is the LDL receptor, which is responsible for the uptake and catabolism of LDL, as well as chylomicron and VLDL remnants (4). The level of LDL receptor expression in the liver plays a major role in regulating the plasma level of cholesterol. A second pathway for clearance of apoE-containing chylomicron and VLDL remnants is called the LDL receptor-related protein (LRP). This receptor is particularly important when there is a deficiency of LDL receptors (5).
Lipid modifying enzymes and lipid transport proteins also play a major role in lipoprotein metabolism and potentially in atherosclerosis. Lipoprotein lipase (LPL) is an enzyme that hydrolyzes triglycerides in chylomicrons and VLDL. It is bound to the surface of the capillary endothelium, especially in muscle and adipose tissue, and binds to the chylomicrons as they traverse the capillary bed. A required cofactor for LPL is apoC-II, which is found on the chylomicrons. The LPL-mediated hydrolysis of triglycerides generates free fatty acids when they enter the tissue to serve as a source of energy or fat storage. The resulting “chylomicron remnant” is released and eventually taken up by the liver. Hepatic lipase is synthesized primarily by the liver, where it is anchored to the vascular endothelium. It is involved in the hydrolyzing of triglycerides in chylomicron remnants, IDL, and HDL as well as phospholipids in HDL2 (6). Lecithin-cholesterol acyltransferase (LCAT) converts free cholesterol to cholesteryl ester on lipoproteins (especially HDL) by transferring fatty acids from phospholipids to cholesterol (7). The cholesteryl ester transfer protein (CETP) transfers cholesteryl esters and other lipids among lipoproteins (8). One major role is thought to be the transfer of cholesteryl esters from HDL (formed as a result of LCAT activity) to VLDL and IDL in exchange for triglycerides. This may be a major pathway by which cholesterol obtained from cells by HDL is eventually returned to the liver in a process that has been termed “reverse cholesterol transport.” However, some cholesteryl esters are transferred by CETP to VLDL and LDL, and therefore CETP could promote atherogenesis; the relationship of CETP to atherosclerosis remains uncertain. In summary, these lipoprotein-modifying enzymes and lipid transport enzymes act in concert to modulate lipoprotein metabolism and probably have important effects on atherosclerosis.
Rationale for Strategies for Cholesterol Lowering
Multiple randomized, controlled clinical trials have demonstrated the benefit of cholesterol reduction in the secondary prevention of cardiovascular events (i.e., in those who already have documented CHD or other atherosclerotic cardiovascular disease). The Coronary Drug Project demonstrated a modest benefit of niacin in reducing nonfatal myocardial infarction (MI) after 6 years of treatment (9) and in reducing total mortality after 15 years of follow-up (10). The POSCH trial
employed the surgical technique of partial ileal bypass surgery to reduce LDL cholesterol levels and demonstrated a significant 35% relative reduction in fatal CHD and nonfatal MI, although not in total mortality (the primary endpoint of the trial) (11).
employed the surgical technique of partial ileal bypass surgery to reduce LDL cholesterol levels and demonstrated a significant 35% relative reduction in fatal CHD and nonfatal MI, although not in total mortality (the primary endpoint of the trial) (11).
Three more recent secondary prevention trials utilized HMGCoA reductase inhibitors (statins). The Scandinavian Simvastatin Survival Study (4S) (12) was designed to address whether cholesterol reduction with simvastatin in people with CHD and elevated cholesterol would reduce total mortality. The trial enrolled 4,444 subjects with CHD whose total cholesterol levels were between 212 and 310 mg/dL, and who were randomized to placebo or simvastatin for a mean of 5.4 years. There was a highly significant 30% relative reduction in total mortality in the simvastatin-treated group (P <0.00001). The relative risk of a major coronary event was reduced by 44%, and revascularization procedures were decreased by 34%. Importantly, the quartile with the lowest LDL cholesterol levels at baseline had proportionately as much benefit from treatment as the highest quartile (13). An economic analysis based on the 4S study concluded that the reduction in hospital costs alone as a result of the treatment would offset the cost of the medication (14).
The majority of patients with CHD, however, do not have such elevated cholesterol levels; in fact, approximately 35% of all people with CHD have total cholesterol levels less than 200 mg/dL (15). Therefore, another major trial, the Cholesterol and Recurrent Events (CARE) Study (16), addressed whether patients with prior MI and “average” cholesterol levels would benefit from further cholesterol reduction with pravastatin. In this trial, 4,159 patients who were 3 to 20 months post-MI and had total cholesterol levels <240 mg/dL were randomized to placebo or pravastatin 40 mg daily and followed for an average of 5 years. The mean baseline total cholesterol level was 209 mg/dL in each group, and the mean baseline LDL cholesterol level was only 139 mg/dL (range 115 to 174 mg/dL). After 5 years, there were 274 subjects in the placebo group who experienced a nonfatal MI or CHD death (the primary endpoint), compared with 212 subjects in the pravastatin-treated group, for a 24% reduction in relative risk (P = 0.003). Revascularization procedures were reduced by 27%. These results demonstrated that the benefit of cholesterol-lowering therapy extends even to those patients with CHD who have average cholesterol levels. The LIPID trial (17) was an even larger (9,014 patients) secondary prevention study of patients with CHD who had baseline cholesterol levels of 155 to 271 mg/dL. Subjects were randomized to placebo or pravastatin 40 mg and followed for an average of 6 years. Coronary heart disease mortality was reduced by 24% (P <0.001) and overall mortality by 22% (P <0.001), and there were significant reductions in other CHD events (MI, unstable angina, and need for revascularization), as well as strokes.
The benefit of therapies aimed at low HDL cholesterol in patients with CHD was recently addressed in the Veteran Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study (VA-HIT) (18). Treatment with gemfibrozil (1,200 mg daily) in 2,531 patients with CHD, low HDL cholesterol (mean 32 mg/dL), and relatively low LDL cholesterol levels (mean 112 mg/dL) resulted in a 22% reduction in the primary endpoint (nonfatal MI and coronary death) compared to placebo (P = 0.006) after an average of 5.1 years. Notably, gemfibrozil resulted in a 6% increase in HDL cholesterol and a 31% decrease in triglycerides but no change in LDL cholesterol levels. This important study extends the indication for lipid-modifying drug therapy in patients with CHD to those with well-controlled LDL cholesterol but low HDL cholesterol.
Primary prevention of CHD is extremely important, as approximately one-quarter to one-third of first MIs result in death (19), precluding the opportunity for secondary prevention. Randomized clinical trials support the use of cholesterol-lowering drug therapy in primary prevention as well. In the World Health Organization cooperative trial using clofibrate in hypercholesterolemic men (20), there was a 25% reduction in relative risk of nonfatal MI (the primary endpoint) after 5 years, although a substantial 47% increase in noncardiovascular deaths. In the Lipid Research Clinics (LRC) primary prevention trial with cholestyramine in hypercholesterolemic men (21,22), combined fatal CHD and nonfatal MI (the primary endpoint) were reduced by 19%. The Helsinki Heart Study (23) using gemfibrozil in men with elevated “non-HDL cholesterol” >200 mg/dL demonstrated a significant 34% reduction in combined fatal and nonfatal MI.
Two more recent trials with statins have confirmed the efficacy of cholesterol lowering in primary prevention. The West of Scotland Coronary Prevention Study (WOSCOPS) (24) was performed in 6,595 healthy Scottish men ages 45 to 64 with total cholesterol levels >252 mg/dL and LDL cholesterol levels 174 to 232 mg/dL. Subjects were randomized to pravastatin 40 mg/day versus placebo and followed for an average of 5 years. The primary endpoint of the study was nonfatal MI or CHD death. There were 248 such CHD events in the placebo group and 174 CHD events in the pravastatin group, resulting in a 31% reduction in relative risk of nonfatal MI or CHD death (P <0.001). In addition, there was a significant 32% reduction in cardiovascular mortality and a 37% reduction in revascularization procedures. Importantly, the relative risk of death from any cause (total mortality) was reduced by 22% in the pravastatin-treated group. This trial clearly established that drug therapy for hypercholesterolemia decreases the risk of cardiovascular events and total mortality, even in people who do not have prior evidence of CHD.
The AFCAPS/TexCAPS trials extended these findings for primary prevention into a population with average cholesterol levels (25). A total of 6,608 men and women without clinical cardiovascular disease, with an LDL cholesterol level of 130 to 190 mg/dL, and with HDL cholesterol levels <45 mg/dL in men and <47 mg/dL in women were randomized to lovastatin 20 mg or placebo for an average of 5.2 years. There was a 37% relative risk reduction (P <0.001) in the primary endpoint (defined as either fatal or nonfatal MI, unstable angina, or sudden cardiac death) in the lovastatin-treated group. Revascularizations were also significantly reduced by 33%. Interestingly, only 17% of the subjects in this trial would have met current National Cholesterol Education Program (NCEP) guidelines for drug therapy. Therefore, the major clinical challenge in the use of drug therapy for cholesterol in primary prevention is the accurate identification of individuals who are likely to develop clinical CHD and who are therefore most likely to benefit from drug therapy.
One question that was generated by these prior statin trials was the potential merits of more intensive LDL cholesterol lowering. Findings from the Heart Protection Study provided preliminary evidence that this indeed might be the case. This study enrolled 20,536 patients with coronary artery disease (CAD), vascular disease, or diabetes and randomized them to simvastatin or placebo for 5 years. In the subgroup of patients with a baseline LDL cholesterol less than 117 mg/dL (6,793 patients), whose mean LDL cholesterol level was lowered to 70 mg/dL on simvastatin, there was still a 21% reduction in major vascular events (fatal or nonfatal MI, stroke, or revascularization) (26). More recently, the PROVE-IT trial compared intensive LDL cholesterol lowering with atorvastatin 80 mg to less-intensive LDL cholesterol lowering with pravastatin 40 mg in 4,162 patients who had just been hospitalized for an acute coronary syndrome. Those assigned to atorvastatin experienced a decrease in mean LDL cholesterol to 62 mg/dL versus a decrease to 95 mg/dL in the pravastatin group, The primary event rate (combined endpoint of all-cause death, nonfatal MI,
unstable angina requiring hospitalization, revascularization within 30 days, or stroke) was 16% lower (P = 0.005) with more intensive LDL cholesterol lowering (27). Most recently the Treating to New Targets (TNT) trial addressed the issue of more-versus less-intensive LDL cholesterol lowering in stable patients with established CAD and an LDL cholesterol >130 mg/dL (28). This trial enrolled 10,001 patients with CHD randomized them to atorvastatin 80 mg or atorvastatin 10 mg, and followed them for a median of 4.9 years. Those assigned to 80 mg of atorvastatin experienced a decrease in LDL cholesterol to 77 mg/dL, as compared to 101 mg/dL in the group receiving the 10 mg of atorvastatin. More-intensive LDL cholesterol lowering in this trial led to a 22% lower (P <0.001) incidence of the primary endpoint (time to first major cardiovascular event, defined as CHD-death, nonfatal non-procedural-related MI, resuscitated cardiac arrest, and fatal and nonfatal stroke). Overall mortality, however, was not significantly different between groups.
unstable angina requiring hospitalization, revascularization within 30 days, or stroke) was 16% lower (P = 0.005) with more intensive LDL cholesterol lowering (27). Most recently the Treating to New Targets (TNT) trial addressed the issue of more-versus less-intensive LDL cholesterol lowering in stable patients with established CAD and an LDL cholesterol >130 mg/dL (28). This trial enrolled 10,001 patients with CHD randomized them to atorvastatin 80 mg or atorvastatin 10 mg, and followed them for a median of 4.9 years. Those assigned to 80 mg of atorvastatin experienced a decrease in LDL cholesterol to 77 mg/dL, as compared to 101 mg/dL in the group receiving the 10 mg of atorvastatin. More-intensive LDL cholesterol lowering in this trial led to a 22% lower (P <0.001) incidence of the primary endpoint (time to first major cardiovascular event, defined as CHD-death, nonfatal non-procedural-related MI, resuscitated cardiac arrest, and fatal and nonfatal stroke). Overall mortality, however, was not significantly different between groups.
In summary, the overall body of clinical data strongly supports the use of drug therapy for LDL cholesterol reduction in virtually all patients with established atherosclerotic vascular disease or diabetes and in certain higher risk groups without vascular disease. Aggressive cholesterol reduction in patients with CHD or other atherosclerotic disease is now the standard of care, as agreed on in a joint statement issued by the American Heart Association (AHA) and the American College of Cardiology (ACC) (29). A recent update to these AHA/ACC guidelines incorporated the findings from newer trials (30). With regard to intensive LDL cholesterol lowering, intensive LDL cholesterol lowering to achieve a level <70 mg/dL is now considered a therapeutic option for patients at very high risk, such as those with established cardiovascular disease plus (a) multiple risk factors (particularly diabetes), (b) severe and poorly controlled risk factors (especially continued cigarette smoking), (c) multiple features of the metabolic syndrome (particularly low HDL cholesterol and elevated triglycerides), and (d) a recent acute coronary syndrome.
Background About Therapy for Lipid Disorders
Nonpharmacologic Therapy
Dietary modification is an important component of the effective management of patients with lipid disorders. It is important for the physician to make a general assessment of the patient’s diet, to provide suggestions for improvement, and to recognize whether a patient may benefit from referral to a dietician for more intensive counseling. The dietary approach depends on the type of hyperlipidemia. For predominant hypercholesterolemia, the major approach is restriction of saturated fat intake.
Current recommendations regarding total and saturated fat consumption are available from the NCEP Expert Panel (31), the AHA (32), and the U.S. Department of Health and Human Services (DHHS) and the U.S. Department of Agriculture (USDA) (33). The NCEP guidelines recommend that 25% to 35% of calories should be derived from fat, with <7% of calories from saturated fat. The AHA Dietary guidelines focus on the restriction of both saturated fat to <10% (or <7% for those with cardiovascular disease, diabetes, or elevated LDL cholesterol). The DHHS executive summary recommends consuming 20% to 35% of calories from fat, with <10% from saturated fats. All three of these guidelines also recommend the general restriction of trans fat because this is known to elevate total and LDL cholesterol while lowering HDL cholesterol.
The majority of patients have relatively modest (<10%) decreases in LDL cholesterol levels with restriction of saturated fat intake to <10% of total calories. If therapeutic goals for LDL cholesterol are not reached after 3 to 6 months with this degree of restriction, the patient may be counseled on further restriction in saturated fat to <7% of total calories. All patients with established atherosclerotic cardiovascular disease should be instructed directly in restricting saturated fat intake to <7%. Many people experience a decrease in HDL cholesterol when they decrease the amount of total and saturated fat in their diet. The clinical implications of this decrease in HDL-C are not clear, and patients should be reassured that a low-fat diet is nevertheless beneficial in terms of overall cardiovascular risk. Substituting unsaturated fat for saturated fat may lower LDL cholesterol without simultaneously lowering HDL cholesterol (34). This dietary principle partly underlies the Mediterranean style of diet, which has been associated with reduced cardiovascular event rates in two randomized controlled trials (35,36). The most recent guidelines from the NCEP have liberalized to a certain degree the intake of unsaturated fat (up to 10% polyunsaturated fat and up to 20% monounsaturated fat intake) (37). For patients with mild to moderate hypertriglyceridemia, dietary counseling should also include restriction of simple carbohydrates. Treatment of severe hypertriglyceridemia (>1,000 mg/dL) includes restriction of all fat intake, both saturated and unsaturated. Regular aerobic exercise can have a positive effect on lipids. Elevated triglycerides are especially sensitive to aerobic exercise, and people with hypertriglyceridemia can substantially lower their triglycerides by initiating an exercise program. The effect of exercise on LDL cholesterol levels is more modest. Although widely believed to be a method for raising HDL cholesterol, the effects of aerobic exercise on HDL are relatively modest in most individuals. Patients should also be reminded that aerobic exercise has cardiovascular benefits that extend well beyond its effect on lipid levels (38). Obesity is often associated with hyperlipidemia, especially with elevated triglycerides and low HDL cholesterol. In people who are overweight, weight loss can have a significant favorable impact on the lipid profile and should be actively encouraged. Along with counseling on other dietary issues, a dietician should also advise patients on the caloric restriction necessary for effective weight loss.
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